Nerve regeneration is a complex biological process. The degenerative processes following damage to nerves in the central and peripheral nervous system are similar in some respects but different in others. One of the largest differences is that peripheral nerves have a much greater capacity to regenerate their axons following nerve injury (Fenrich, K. et al. 2004, Can J Neurol Sci. 31(2):142).
Schmidt and Leach (2003, Annu. Rev. Biomed. Eng. 5:293) have recently reviewed a number of ways of treating nerve injuries. Current treatments for injury-induced nerve defects typically rely on donor tissues obtained from the patient. This has raised the issues of loss of function at the donor sites, formation of potentially painful neuromas, structural differences between donor and recipient nerves and a shortage of graft material for extensive repair. To circumvent these problems, synthetic nerve guide conduits (NGCs) have been developed to bridge the nerve gaps by securing the severed nerve stumps into the two ends of the conduit (U.S. Pat. No. 5,019,087). A number of devices, such as, for example, Integra Neurosciences Type I collage tube and SaluMedica's SaluBridge™ Nerve Cuff have been approved by the US Food and Drug Agency. These devices, however, are reserved for treatment of relatively short nerve defects, and in most cases the synthetic conduits do not function as well as nerve autografts (Schmidt & Leach 2003, Annu. Rev. Biomed. Eng. 5:293).
Several tissue-engineering approaches have been proposed to enhance the performance of NGCs, which include delivering neurotrophic factors within hollow tubes. Filling silicone NGCs with dialyzed plasma resulted in a three to fivefold increase in functional restitution at eight weeks compared to NGCs filled with phosphate buffered saline (Williams et al. 1987, J. Comparative Neurology 264:284). Alternatively, neurotrophic factors such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), fibroblast growth factor (FGF), glial growth factor (GFG) and ciliary neurotrophic factor (CNTF) delivered within a conduit may significantly increase the morphological and/or functional recovery of transected and repaired nerves.
NGF is the first and best-characterized nerve-derived factor and acts on a relatively limited variety of neuronal populations, including sympathetic, subpopulations of sensory neurons of peripheral nervous system and striatial and septal cholinergic neurons in the brain (Terenghi, G. 1999, J. Anat 194:1-14). In normal circumstances, NGF is present at a very low concentration but rapidly increases in the experimental nerve injury animal model. NGF is produced mainly by the target tissue and Schwann cells in the distal stump of damaged nerves and then transported in a retrograde manner to the cell soma before acting on receptors on neurons and producing the neurotrophic effects. In peripheral neuropathies, such transport within diseased nerves may be affected, being reduced or totally blocked. While delivery of NGF promotes nerve regeneration within conduits at an early stage, the promoting effect may not last after one month, probably due to the rapid decline of NGF concentrations in the conduit caused by the degradation in aqueous media at 37° C., leakage from the conduit and/or dilution by entering fluids. Furthermore, the timing of the introduction of neurotrophic factors into NGCs has a significant influence on the healing or regenerative processes: introducing various agents too early or too late may inhibit the regenerative process (U.S. Pat. No. 5,584,885).
The cell bodies of sensory neurons are located in dorsal root ganglia (DRG), nodules at the distal end of the dorsal root of each spinal nerve. Within the dural sheath and surrounded by the cerebral spinal fluid (CSF), dorsal and ventral nerve roots leave through the intervertebral foramen, where the dorsal root forms the dorsal root ganglion and thereafter joins the ventral root to form the spinal nerve root. Morphologically, a somatosensory neuron in DRG has a unipolar structure, with a connection to the central nervous system (CNS) by a long ascending axon within the spinal cord, and to the peripheral nervous system (PNS) by a second axon branch descending through the spinal nerve root and further out into a peripheral nerve. Functionally, DRG neurons are heterogeneous, signaling receptor-transduced stimuli of diverse sensory modalities that range from touch, temperature, pain to proprioception.